Heat stress significantly reduces orthostatic tolerance (i.e. fainting) in humans resulting in a high probability of injury when these two stressors are combined. The mechanism(s) causing this response are unknown. In the parent grant we tested the hypothesis that human baroreflex function was impaired during hyperthermic exposure and this contributed to the reduction of orthostatic tolerance observed in this thermal condition. As a result of that work we identified that whole body heating did not alter baroreflex control of heart rate or muscle sympathetic nerve activity. However, preliminary data suggested that heating might attenuate vasoconstrictor responsiveness. Thus, despite an appropriate neural drive during a hypotensive challenge in the heat, the elevation in vascular resistance may be impaired and thereby predispose the individual to fainting. This hypothesized blunted elevation in vascular resistance becomes even more detrimental in maintaining orthostatic tolerance when coupled with proposed heat induced alterations in the Frank-Starling curve, that likely contribute to a greater fall in blood pressure during orthostasis, as well as impaired cerebrovascular autoregulation. Given this background, the primary objective of this proposal is to test the following hypotheses. A) Heat stress shifts the operating point on the Frank-Starling curve to a steeper location such that for the same reduction in ventricular filling pressure during orthostasis there will be a greater reduction in stroke volume, and thus blood pressure, in the heated condition. B) Heat stress impairs pre- and post-synaptic responses such that during an orthostatic challenge the elevation in vascular resistance is attenuated, relative to normothermia, and thus blood pressure regulation will be further impaired. C) Heat stress shifts the cerebrovascular autoregulatory curve, that when combined with a reduction in blood pressure during orthostasis, result in the blood pressure operating point residing on the descending limb of the autoregulatory curve. Upon completion of these studies valuable information will be obtained regarding the etiology of heat-induced reductions in orthostatic tolerance in humans.